title: Alternatively spliced tissue factor promotes breast cancer growth in a β1 integrin-dependent manner.
abstract: Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression. We are unique in reporting that asTF, but not flTF, strongly associates with both tumor size and grade, and induces BrCa cell proliferation by binding to β1 integrins. asTF promotes oncogenic gene expression, anchorage-independent growth, and strongly up-regulates tumor expansion in a luminal BrCa model. In basal BrCa cells that constitutively express both TF isoforms, asTF blockade reduces tumor growth and proliferation in vivo. We propose that asTF plays a major role in BrCa progression acting as an autocrine factor that promotes tumor progression. Targeting asTF may comprise a previously unexplored therapeutic strategy in BrCa that stems tumor growth, yet does not impair normal hemostasis.
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
authors.forename: Begüm
authors.initials: B
authors.lastname: Kocatürk
authors.forename: Yascha W
authors.initials: YW
authors.lastname: Van den Berg
authors.forename: Chris
authors.initials: C
authors.lastname: Tieken
authors.forename: J Sven D
authors.initials: JS
authors.lastname: Mieog
authors.forename: Esther M
authors.initials: EM
authors.lastname: de Kruijf
authors.forename: Charla C
authors.initials: CC
authors.lastname: Engels
authors.forename: Martijn A
authors.initials: MA
authors.lastname: van der Ent
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kuppen
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Van de Velde
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
authors.forename: Pieter H
authors.initials: PH
authors.lastname: Reitsma
authors.forename: Susanne
authors.initials: S
authors.lastname: Osanto
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Liefers
authors.forename: Vladimir Y
authors.initials: VY
authors.lastname: Bogdanov
authors.forename: Henri H
authors.initials: HH
authors.lastname: Versteeg
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D013925:Thromboplastin / Q000235:genetics / Q000502:physiology*
chemical_list: D019012:Integrin beta1; D013925:Thromboplastin
keywords: outside-in signaling; regulated pre-mRNA processing